DESCRIPTION: The overall goal of this proposal is to develop a new process for more complete comminution of urinary calculi (stones) by combining histotripsy acoustic fields with conventional shockwaves. Preliminary evidence shows that histotripsy and lithotripsy can operate synergistically in multiple ways to enhance stone fragmentation. Histotripsy ultrasound therapy is a method of soft tissue ablation where extremely intense acoustic bursts cause microscopic bubbles to form and collapse energetically (cavitation) disrupting cell membranes and fragmenting nearby tissues. Using short bursts up to a few tens of acoustic cycles and highly focused sound fields allows cavitation to be controlled for precise ablation. Histotripsy research has yielded a greater understanding of acoustically generated cavitation and techniques for the enhancement and suppression of cavitation activity, which have been employed to increase the ablation rate and to protect adjacent tissue from collateral injury. When applied directly to stones, histotripsy produces rapid surface erosion with the generation of only microscopic debris. In combination with shockwaves, cavitation amplifying histotripsy sequences are expected to enhance stone comminution while suppressing sequences will actively protect surrounding kidney parenchyma from damage. While shockwave lithotripsy (SWL) has been an invaluable tool in the treatment of urinary stones, success rates have been consistently worse than more invasive interventions. SWL fails to achieve stone free status in 20-40% of patients at 3 month follow up and even successful procedures may involve the painful passage of fragments which have been only partially disintegrated. Large stones (> 20 mm diameter), stones of difficult composition (i.e. cystine), and stones located in the lower pole all have worse outcomes further discouraging treatment with SWL. Using histotripsy to control the cavitation environment immediately near a stone and in neighboring tissues allows a decoupling of cavitational and non-cavitational SWL mechanisms otherwise closely intertwined. This will aid in their study and optimization ultimately leading to more efficient stone comminution strategies producing better treatment outcomes and opening up traditionally difficult stones to the option of SWL.